Repeated dose toxicity neurotoxicity

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test 424 Neurotoxicity study in rodents... 

The standard repeated dose toxicity guideline studies include a number of parameters relevant for the evaluation of a substance s neurotoxic potential. In addition to these standard... 

The TGD (EC 2003), Chapter 3.9, addresses repeated dose toxicity and provides guidance on data requirements, evaluation of data, and dose-response assessment. Included is a section on specific system/organ toxicity dealing with guidance on investigation of neurotoxicity (Section 4.7.7.3) and... 

Use of Information from Repeated Dose Toxicity Studies in the Hazard Assessment of Neurotoxicity... 

The details of several other toxicological tests (namely, repeated-dose toxicity, subchronic toxicity, chronic toxicity, genotoxicity, mutagenicity, teratogenicity, carcinogenicity, neurotoxicity, and ecotoxicology) and the methods, purposes, and importance of safety evaluation studies to achieve human health have been discussed... 

Repeat-dose neurotoxicity studies may identify behavioral effects or impaired nerve functions that can interfere with mating or maternal care. Developmental neurotoxicity studies have been conducted for specific pesticide classes, following requirements of US-EPA. If such a study is available it can be examined not only for the study-specific endpoints on the developing brain but also compared to the prenatal toxicity study and the two-generation smdy with respect to general endpoints of pre- and postnatal development, respectively. 

Repeated inhalation or oral exposures to moderate to high doses of -butyl acetate and -butanol are well tolerated. These aforementioned molecules are readily and rapidly metabolized to -butyric acid. The no-observed-effect level (NOEL) for repeated dose oral exposure to -butanol was 125 mg kg day. In a 90 day inhalation study in rats with -butyl acetate a NOEL of 500 ppm was reported for systemic effects, and a NOEL of 3000 ppm (highest dose tested) was reported for postexposure neurotoxicity based on functional observational battery endpoints, quantitative motor activity, neuropathy, and sched-uled-controlled operant behavior endpoints. Results of inhalation studies conducted on -butanol and -butyl acetate were negative for inducing reproductive and developmental toxicity. The NOEL for female reproductive toxicity was 6000 ppm with -butanol and 1500 ppm for -butyl acetate. In a 90 day repeated-dose inhalation toxicity study with butyl acetate the NOEL for male reproductive toxicity was 3000 ppm. For developmental toxicity, a NOEL of 3500 ppm was observed with -butanol and a NOEL of 1500 ppm (the highest exposure tested) was seen in both rats and rabbits following exposure to -butyl acetate. 

Cholinesterase inhibition can sometimes persist for weeks thus, repeated exposures to small amounts of this material may result in accumulation of acetylcholinesterase inhibition with possible sudden-onset acute toxicity. Chlorpyrifos may be capable of causing organophosphate-induced delayed neurotoxicity in humans a massive overdose resulted in signs characteristic of delayed neurotoxicity. Animal studies generally indicate, however, that doses several times higher than the LD50 would be required to initiate delayed neurotoxicity. 

As with most organophosphorus insecticides, acute toxicity is predominant. However tolerance to repeated exposures can occur. The no-observed-adverse-effect level (NOAEL) established from a rabbit developmental toxicity study was 50 mg kg day based on maternal toxicity (i.e., reduced body weight gain). Developmental toxicity studies were negative in rats and rabbits. A two-generation reproductive toxicity study in rats showed no increased sensitivity in pups compared to dams. Repeated exposure to malathion does not cause delayed neurotoxicity. The NOAEL of 2.4 mg kg day was established based on plasma cholinesterase inhibition in a long-term dosing study in rats. 

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